The antisense approach attempts therapeutic intervention via purine/pyrimidine sequence-specific interception of cellular components that interact with DNA or RNA elements in vivo. The approach entered a new era in 1998 with the first FDA approval of an antisense therapeutic, fomivirsen sodium (Isis/Novartis CIBA Vision), for the treatment of cytomegaloviral retinitis in AIDS patients. There are currently at least 10 more antisense therapies in Phase II or III clinical trials. Each of the areas of Phase II/Phase III clinical antisense research requires efficient methods for the synthesis, purification, and characterization of the oligomeric antisense agent, and of four or more monomeric nucleoside analog precursors. The research of this NIH MBRS laboratory for antisense research now focuses on the development of such efficient methods, including broadening the stereoselective, radical-mediated Chu-Tam approach to 3'-C-substituted nucleotide analogs, developing general, convergent syntheses of antisense precursor monomers (e.g., via adaptations of the Stork-Just approach to 3',5'-substituted ribofuranose analogs), identifying and designing potential new first generation antisense therapeutics in the antiinfectives area, and developing methodologies to effectively rank the potencies of antisense agents via in vitro assay.